original article

Pituitary gigantism: a case

series from Hospital de San
José (Bogotá, Colombia)

1 Head of the Endocrinology

William Rojas García1
http://orcid.org/0000-0001-7120-9432 Unit, Hospital de San José;
associate professor, Fundación
Henry Tovar Cortes2 Universitaria de Ciencias de la
http://orcid.org/0000-0003-0591-2562
Salud, Bogotá, DC, Colombia
Andrés Florez Romero3 2 Hospital de San José;

http://orcid.org/0000-0001-6946-7993 assistant professor, Fundación

Universitaria de Ciencias de la
Salud, Bogotá, DC, Colombia
ABSTRACT 3 Hospital de San José,

Bogotá, DC, Colombia

Introduction: Gigantism is a rare pediatric disease characterized by increased production of growth
hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal
abnormalities, and multiple comorbidities. Materials and methods: Case series of 6 male patients with
gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010
and 2016. Results: All patients had macroadenomas and their mean final height was 2.01 m. The mean age
at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%).
All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm.
All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including
radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant
(n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1
normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl
hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), Correspondence to:
fulfilling the diagnostic criteria of familial isolated pituitary adenoma. Conclusions: This is the largest case Andrés Florez Romero
Hospital de San José, Bogotá,
series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice DC, Colombia Street 10 #. 18-
procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be 75
considered in familial cases of GH-producing adenomas. Arch Endocrinol Metab. 2019;63(4):385-93 andresflorez25@hotmail.com

Received on Jan/3/2018
Accepted on Apr/24/2019
Keywords
Pituitary diseases; gigantism; growth hormone; pituitary neoplasms; acromegaly DOI: 10.20945/2359-3997000000150

INTRODUCTION treatment for gigantism is transsphenoidal surgery

G igantism is a rare pediatric disease, with an incidence of 8

to 11 cases per million individuals per year.
This disease is characterized by increased production of
growth hormone (GH) when the epiphyses are still open,
and in most cases is secondary to a pituitary adenoma (1).
Gigantism can occur sporadically or have a hereditary
component (2); in a case series by Rostomyan and cols.
(3), a genetic cause was identified in 46% of the cases, of
which the most common was a mutation in the
hydrocarbon receptor-interacting protein (AIP) gene
(28%), followed by X-linked acrogigantism (X-LAG;
10%). McCune-Albright syndrome (5%), Carney
(TSS) (4). However, complete remission of the disease
is not usually achieved with surgical intervention alone
and pharmacological therapy becomes necessary (2,5-
7), of which somatostatin analogues (SSA) is the most
common. If no response is obtained with SSAs,
dopamine receptor agonists (cabergoline) or GH
receptor antagonists (pegvisomant) can be added (8-
10). In cases that fail to respond to surgery and
pharmacological treatment, radiotherapy is used;
however, the risk of hypopituitarism should be taken
into account (8).
The purpose of this study is to present 6 cases of
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complex (1%), and multiple endocrine neoplasia type 1
(1%) are less common causes of gigantism (3). The main
symptom of the disease is abnormal accelerated growth
affecting the musculoskeletal system associated with
some other comorbidities (1). The first-choice
gigantism treated in Colombia, including a 6-year
follow-up and treatment outcomes. We also present the
clinical history of 2 patients with gigantism secondary
to familial isolated pituitary adenoma (FIPA) and AIP
mutation.

Arch Endocrinol Metab. 2019;63/4 385

 Pituitary gigantism: a case series

MATERIALS AND METHODS using the Colombian height and weight chart (11).
We present a review of 6 cases of gigantism secondary
Biochemical and imaging diagnostic tests included
increased serum GH and insulin-like growth factor-1
to pituitary adenomas, managed at the Endocrinology
(IGF-1) levels and evidence of a pituitary adenoma in
Department of Hospital de San José (Bogotá, Colombia),
the sella turcica on magnetic resonance imaging (MRI)
a tertiary referral center, between January 2010 and
(2,3). Since no standard criteria are available to define
December 2016. At this institution, we see an average of
controlled disease in patients in gigantism, the
110 cases of acromegaly per year. All patients provided a
biochemical diagnostic criteria for acromegaly were
written informed consent for picture release. Data,
used for follow-up (12), i.e., IGF-1 in the normal range
including medical history and laboratory results, were
and GH level below 1 ng/mL.
collected retrospectively. Additional information was
obtained directly from the patients.
AIP testing was requested from all patients but was RESULTS
only obtained from patients #1 and #5 (Table 1), In all, 6 cases of gigantism were managed at our Unit
confirming a diagnosis of FIPA with AIP mutation. Total according to established criteria between 2010 and 2016.
genomic DNA extraction was performed from venous The patients were all male and had a mean age at
blood samples using conventional techniques, and an symptom onset of 12.3 years. Their mean age at diagnosis
analysis of the complete AIP gene coding sequence was 16 years, and their mean final height was 2.01 meters
(exons 1-6) was done including all exon-intron junctions. (m). All patients had pituitary macroadenomas. The
The exon sequences were compared against the GenBank tumor sizes are described in Table 1. No record is
accession number NM_003977.2, with the A of the ATG available regarding the tumor sizes of patients #3 and #5
translation initiation codon in position 1. To test for the since they arrived at our center after undergoing surgical
c.504G>A (p.Trp168*) variant of the AIP gene, total procedures at another institution, so initial MRI reports
genomic DNA was extracted from venous blood samples were not available. The most common symptoms were
following a conventional technique. A conventional PCR headache and hyperhidrosis, which were present in 4
assay was developed to amplify exon 4 of the AIP gene patients, followed by acroparesthesia in 3 patients, and
(wild type sequence, ENST00000279146) from DNA in arthralgia and fatigue in 2 patients each.
both cases. The amplified product was purified and All 6 patients showed acral changes. One patient
sequenced. (patient #1) had visual impairment secondary to
The diagnosis of gigantism was established based compression of the optic chiasm by the adenoma. Only 2
on a height above 2 or more standard deviations for patients (#1 and #5), had a family history of tall stature or
age (> 97th percentile), or a final height greater than 2 other endocrine disorders. Table 1 presents a summary of
standard deviations above the general population, the main clinical and laboratory findings of each patient.

Table 1. Demographic characteristics of patients with gigantism

Age at Age at Final Height Height Z-score Z-score Body BMI Tumor
symptom - mean
Patient Gender diagnosis height - father population weight (kg/ size ST RT MED
onset mother parental
(years) (meters) (meters) mean (kg) m2) (mm)
(years) (meters) height
1 M 12 12 1.96 1.71 NA 4.2 NA 107 27.8 5 x 17.3 TSS YES LAR,
x 29 (2)1 PEG
2 M 13 21 2.2 1.68 1.68 5.9 6.17 108 22.3 18 x 20 FC NO NA
x 20
3 M 11 11 2.1 1.58 1.5 4.5 6.69 103 23.3 NA FC YES OCT,
CAB
4 M 14 17 1.93 1.7 1.5 2.26 3.63 75 20.35 16 x 15 TSS NO OCT
x 17
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5 M 14 23 1.91 NA 1.53 1.98 NA 122 33 NA TSS YES NO

6 M 10 12 2 1.65 1.5 3.2 2.78 107 27.2 25 x 20 TSS YES LAR,
x 20 (2)1 PEG
CAB: Cabergoline, FC: Frontal craniotomy, LAR: Lanreotide, M: Male, MED: Medical treatment, NA: Not available, OCT: octreotide long-acting (LAR), PEG: Pegvisomant, ST: Surgical treatment, RT:

Radiotherapy, TSS: Transsphenoidal surgery. 1. Number of surgeries performed.

386 Arch Endocrinol Metab. 2019;63/4

 Pituitary gigantism: a case series

All 6 patients were initially managed with surgical
resection of the tumor, including TSS in 4 patients (#1,
#4, #5, and #6) and frontal craniotomy in 2 patients (#2
and #3). Two patients required a second surgical
intervention via TSS (patients #1 and #6).
Immunohistochemistry confirmed exclusive production
of GH by the adenomas in all patients, and none of the
patients had increased serum prolactin.
All 6 patients had only partial improvement of
symptoms after surgery and required other treatments.
Four patients (#1, #3, #5, and #6) received radiotherapy,
and 5 required additional medical management with
SSAs (3 patients with lanreotide Autogel and 2 with
long-acting release [LAR] octreotide). Due to the absence
of clinical response, cabergoline was added to the therapy
in 3 patients (#1, #3, #6) and pegvisomant was added to 2
patients (#1 and #6, both at a dose of
20 mg/day).
Normal GH (< 1 ng/mL) and IGF-1 levels were
achieved in 4 patients, one after frontal craniotomy
(patient #2); one after frontal craniotomy, radiotherapy,
octreotide LAR, and cabergoline (patient #3); and 2 after
TSS, lanreotide Autogel, pegvisomant, and
radiotherapy (patients #1 and #6). One patient (#4),
who received treatment with TSS and octreotide LAR,
showed fluctuating IGF-1 levels, but since he was
asymptomatic, pegvisomant was not recommended.
Patient #5 interrupted the follow-up at our institution.
Four patients (#1, #3, #4, and #6) underwent regular
monitoring for more than 3 years, and their IGF-1
values are presented in Table 2. Patient #3 started
following up at our center after undergoing surgical
intervention, radiotherapy, and pharmacological
treatment at another institution, therefore, his initial
IGF-1 levels at our institution were normal.
Regarding associated comorbidities, one patient
(#5) had class 1 obesity, 2 (#1 and #6) were
overweight, and one (#1) had hyperglycemia.
Cholelithiasis was investigated with hepatobiliary
ultrasound, but none of the patients presented this
comorbidity. No other comorbidities associated with
GH excess were found. Two patients presented
hypopituitarism (patients #1 and #3, who had thyroid
and gonadal dysfunctions, respectively).
Figure 1 shows pictures of 5 out of the 6 patients. A
summary of the clinical history of the 2 patients (#1 and

Table 2. IGF-1 levels (in ng/mL) and upper limit of normal in patients followed up for more than 36 months
Months
Patient 0 6 12 18 24 30 36 42
ng/mL ULN ng/mL ULN ng/mL ULN ng/mL ULN ng/mL ULN ng/mL ULN ng/mL ULN ng/mL ULN
1 794 1.6 824 1.6 1017 2 876 1.7 1084 2.1 692 1.4 700 1.4 130 N
3 61 N 85 N 39 N 26.2 N 25.9 N
4 337 N 367 N 147 N 444 N 501 1.01 303 N 180 N 513 1.03
6 753 1.5 677 1.3 610 1.2 511 1.02 950 1.9 543 1.09 402 N 150 N

N: Normal, ULN: Upper limit of normal.

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Figure 1. Photograph of 5 of the patients. From left to right: patient 1, patient 2, patient 3, patient 5 and patient 6.

Arch Endocrinol Metab. 2019;63/4 387

 Pituitary gigantism: a case series

#5) who had familial pituitary adenomas is presented
below. A genealogical tree of these patients (who
belonged to the same family), from whom a sample of
the AIP gene was requested, is presented in Figure 2.
Patient 1: His symptoms began at the age of 12 years
with headache, hyperhidrosis, lower limb paresthesia, and
tall stature (1.74 m). His initial laboratory tests showed
GH levels greater than 40 ng/mL (reference range 0-5
ng/mL), IGF-1 level 794 ng/mL (reference range 111-498
ng/mL), and normal levels of TSH, free T4, FSH, LH,
prolactin, cortisol, ACTH, and glucose. An MRI of the
sella turcica showed an expansive lesion of 5.0 x 17.3 x
29.0 mm compressing the optic chiasm and infiltrating the
left cavernous sinus (Figures 3A and 3B). Monthly
lanreotide (90 mg, intramuscular) was initiated and TSS
was performed at the age of 12 years.
Immunohistochemistry analysis of the adenoma was
positive for GH. After surgery, the patient persisted with
symptoms and acral growth and presented serum levels of
GH > 40 ng/mL and IGF-1 of 1165 ng/mL; based on that,
the lanreotide dose was increased to 120 mg and
cabergoline 0.5 mg weekly was initiated. A new MRI
showed a residual tumor infiltrating the left cavernous
sinus, and a second TSS was performed at the age of 13
years. Due to poor biochemical control
during postsurgical follow-up, his cabergoline dose was
increased to 2 mg weekly. A follow-up MRI after the
second surgery showed a lesion of 36 x 30 x 20 mm and
optic chiasm compression (Figure 3C). Due to the
increase in tumor size and poor biochemical control,
radiotherapy was performed at the age of 14 years.
Pegvisomant was also initiated and cabergoline was
suspended, resulting in a decrease in IGF-1 levels and
control of the symptoms. A contrast MRI performed 2
years after the radiotherapy is shown in Figure 3D. The
final height of the patient was 1.96 m. Given the
occurrence of gigantism in a second-degree uncle (patient
#5) and acromegaly in a second-degree aunt, an AIP gene
sequencing was requested, which showed the
heterozygous pathogenic variant c.504G>A in exon 4
(p.Trp168*) generating a nonsense substitution of
tryptophan causing a premature stop codon.
Patient 5: The onset of his symptoms occurred at
the age of 14 years, manifesting as tall stature. The
patient was diagnosed with a pituitary macroadenoma
at the age of 23 years and treatment with TSS was
performed. He required radiotherapy at the age of 27
years and used SSA for 1 year. Adequate biochemical
and imaging control were observed at follow-up, and
his final height was 1.91 m. Given the family history

I 87

1 2

II 67 65 62 60 59 57 53 53 51 51 51 56 45
1 2 3 4 5 6 7 8
9 10 11 12 13 14 15
G A 19 31 11 24 28 26 17 16 16 22

III 37 35 30 38 36 42 34 28 26 33 33 27 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
G

IV 13 4m 13 18 3 5 3 16 13 9 9 7 3 14 12 6 5 4 4
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Conventions G: Gigantism
Woman A: Acromegaly
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Man M: Months
Deceased IV 4: Patient 1

(+) variant c. 504G>A (p. Trp168*) AIP gene III 7: Patient 5

X Age (years) III 13: Patient 1 – second-grade aunt

Figure 2. Genealogical family tree with mutation of the AIP gene.

388 Arch Endocrinol Metab. 2019;63/4

 Pituitary gigantism: a case series

of gigantism on a second-degree nephew (patient #1)
and acromegaly on a second-degree female cousin, the
variant c.504G> A (p.Trp168*) of the AIP gene was
tested and resulted positive. The same variant was
tested in the patient’s relatives (patient #1 and patient
#5, who was diagnosed with acromegaly at the age of
25 years), and resulted positive.
DISCUSSION
Between 5-15% of the pediatric pituitary adenomas
produce GH. Most cases (90%) comprise
macroadenomas, and 30-60% are invasive. A higher
frequency in males is reported in the literature (13).
In most recent case series, there was a predominance of
male patients, as in the series by Nagata and cols. (Japan;
7 out of 13 patients [54%]) (14), Creo and Lteif (USA; 9
out of 13 patients [69%]) (15), Rostomyan and cols.
(Belgium; 163 out of 208 patients [78%]) (3), Patt and
cols. (India; 13 out of 14 patients [92%]) (16), Mangupli
and cols. (Venezuela) (6 out of 8 patients [75%]) (6), and
in the present case series (Colombia; 6 out of 6 patients
[100%]). The diagnosis of gigantism is usually
established around the age of 14 years, and was reported
at a mean age of 13.6 years by Creo and Lteif (15), 13
years by Rostomyan and cols. (3), 18 years by Mangupli
and cols. (6), and 21.9 ± 6.1 years by Patt and cols. (16).
In our case series, the diagnosis

A B

C D

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Figure 3. (A) Initial coronal T1-weighted magnetic resonance imaging (MRI). (B) Initial sagittal T1-weighted post-contrast
MRI. (C) Coronal T1-weighted MRI 1 year after the second surgical procedure. (D) Coronal T1-weighted post-contrast
MRI postcontrast 3 years after the second surgical procedure and 2 year after radioterapy plus medical treatment.

Arch Endocrinol Metab. 2019;63/4 389

 Pituitary gigantism: a case series
of gigantism was established at a mean age of 16 years. A
delayed diagnosis of gigantism may occur due to poor
perception of the magnitude of the symptoms, delayed
consultations, and limited knowledge of the disease by
healthcare providers, all of which are important factors in
Latin America. The most common symptoms presented
by our patients were headache (66%) and hyperhidrosis
(66%), unlike the series by Rostomyan and cols. (3), in
which headache was less frequent (23%).
In gigantism, TSS is the first-choice procedure, and
biochemical control is obtained in 70% of the patients
with intrasellar microadenomas, although this rate is
lower with macroadenomas (13). TSS was the most
common procedure performed in our patients (66%), and
none of the patients obtained biochemical control with
this treatment alone. The only case with biochemical
control followed a frontal craniotomy. In the series by
Nagata and cols., 92% (12 out of 13) of the patients were
managed with TSS and 53% (7 out of 13) achieved
biochemical control; this was the case series with best
reported response with TSS (14). In the study by Creo and
Lteif, 92% (12 out of 13) of the patients were treated with
TSS, and only 23% (3 out of 13) achieved biochemical
control (15). In the publication by Rostomyan and cols.,
surgery was performed in 82% (177 out of 208) of the
patients and only 15% obtained biochemical control (3).
In the series by Patt and cols., surgery was performed in
92% (13 out of 14) of the patients and 21% obtained
biochemical control (16). In the cases described by
Mangupli and cols. (6), none of the patients who
underwent surgery obtained control. In our series, surgical
reintervention was required in 33% (2 out of 6) of the
patients, compared with 30% (4 out of 13) in the series by
Creo and Lteif (15) and 64% in the series by Rostomyan
and cols. (3). Only 7.5% of our patients had a biochemical
response to the surgical reintervention, while 2 patients
(33%) presented hypopituitarism with thyroid and
gonadal dysfunction, a rate that is similar to that reported
by Creo and Lteif, who described a 38% rate of
hypopituitarism (5 out of 13 patients) (15).
Given the low biochemical control with surgery,
patients with gigantism usually require additional
management. SSAs were used in 83% of our patients (5
reserved.
out of 6; 3 were treated with lanreotide Autogel and 2
all rights
with octreotide LAR). This finding was similar in the
series by Mangupli and cols. (6), in which 100% (8 out
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of 8) of the patients used SSAs. Still, the use of SSA
was less frequent in other studies: 50% (6 out of 12)
390
of the patients in the series by Creo and Lteif (15), 66.7%
(118 out of 208) reported by Rostomyan and cols. (3), and
23% (3 out of 13) in the study by Nagata and cols. (14).
In our series, none of the patients had biochemical control
with SSA alone, which is aligned to the results by Creo
and Lteif (15) and Mangupli and cols. (6); in contrast, in
the study by Rostomyan and cols., 34% of the patients
were controlled with SSA alone (3). Rates of biochemical
control in patients with acromegaly have been reported at
63.9% with octreotide and 78.1% with lanreotide Autogel
(17). Of note, one case report of a girl with gigantism and
microadenoma showed biochemical control and
disappearance of the tumor with octreotide LAR for 3
years (7). A prospective study conducted in Japan with 32
patients with acromegaly (29 patients) and gigantism (3
patients) assessed the efficacy of lanreotide Autogel;
although separate data for patients with gigantism were
not reported, the efficacy was reported to be similar in
both groups (acromegaly and gigantism) (18).
Dopamine receptor agonists are useful in cases with
associated hyperprolactinemia or as an adjunct therapy to
SSAs in cases with lack of biochemical control and IGF-1
levels up to 1.5 times above the normal range (19). None
of our patients presented hyperprolactinemia, in contrast
to the finding by Mangupli and cols., in which 50% (4 out
of 8) of the patients had hyperprolactinemia
(6). Cabergoline was administered to 3 of our patients,
and biochemical control was obtained in 1 (patient #3)
with concomitant use of octreotide LAR. Cabergoline
was administered to 4 patients by Mangupli and cols.
(6) and 2 patients by Nagata and cols. (14), and none
of the patients obtained biochemical control. The
effectiveness of cabergoline in the management of
gigantism without associated hyperprolactinemia lacks
evidence.
Pegvisomant (a GH receptor antagonist) has been
used in pediatrics to obtain IGF-1 normalization and
symptom improvement in patients without a response
to surgical treatment, radiotherapy, and SSAs, although
the possibility of an increase in tumor size with this
medication should be considered (9,13,20). In a report
of 3 patients treated with pegvisomant, linear growth
was interrupted after 6 months of treatment, and
improvement in diaphoresis and facial features of
acromegaly was observed, along with normalization of
IGF-1 levels in 2 of them, while the other one showed
an increase in tumor size (9). Effectiveness was
confirmed in 2 of our patients in whom this medication
Arch Endocrinol Metab. 2019;63/4
 Pituitary gigantism: a case series

was administrated (patients #1 and #6), a result that is
similar to the one reported by Creo and Lteif (15) and
Mangupli and cols. (6). A lower rate of biochemical
control (50% of the patients) was observed by
Rostomyan and cols. (3), and absence of response was
observed on a single patient treated with pegvisomant
by Nagata and cols. (14). The combination of SSAs
with pegvisomant seems to be the most effective
association for the treatment of gigantism, as reported
by Mangupli and cols. in 8 patients with gigantism.
Early (1 to 4 months) symptom control was observed,
with an absence of tumor growth and normalization of
IGF-1 levels in all patients (6).
Radiotherapy was administered to 66% (4 out of 6)
of our patients, which is a higher rate than reported by
other authors of case series: 46% (6 out of 13) of the
patients by Creo and Lteif (15), 30% (63 out of
208) by Rostomyan and cols. (3), 35% (5 out of 14)
by Patt and cols. (16), and one patient by Mangupli
and cols. (6) and Nagata and cols. (14). The risk of
hypopituitarism, which can occur in 30-50% of the
patients, should be considered (13). Table 3 presents a
comparison of case series of gigantism (3,6,14-16),
including the present study. Most of the cases reported
(78%) include men. The mean age at diagnosis was
15.1 years, and the mean final height was 1.95 m. TSS
was the most frequent initial procedure (83%), and
only 18% of the patients obtained biochemical control
with this procedure alone, while 122 out of 219
patients (56%) required surgical reintervention. Half of
the patients (53%) received SSAs, and only 1
successful case of treatment with SSA monotherapy
was reported. Pegvisomant was administered to 17.5%
of the patients, with IGF-1 normalization in 58% of
them, which is a lower rate than the 67.5% response
reported in a “real world” study in patients with
acromegaly (21), possibly related to inadequate dose
titration. Radiotherapy was used in 30% of the patients
(Table 3), which is a high percentage taking into
account the risk of hypopituitarism in this population.
Familial isolated pituitary adenomas
The diagnosis of FIPA should be suspected when 2 or
more relatives have pituitary adenomas in the absence
of known genetic causes, such as multiple endocrine
neoplasia type 1, Carney complex, or McCune-
Albright syndrome (22). The main causes of FIPA are
X-LAG and AIP gene mutations.

Table 3. Comparison of case series of gigantism reported in the literature

Rostomyan Mangupli and Rojas and
Nagata and cols.
and Daly Patt and cols. Creo and cols. cols.
cols. (Japan) (Colombia) Total
(multicentric) (India) 2015 (USA) 2016 (Venezuela)
2017 2018 (current
2015 2016
study)
Male gender 163/208 14/14 9/13 6/8 7/13 6/6 205/262 (78%)
Mean final height (meters) NA 1.87 2.05 1.9 NA 2.01 1.95
Mean age at diagnosis (years) 13 21.9 ± 6.1 13.6 18 NA 16 15.1
TSS 177/208 13/14 12/13 1/8 12/13 4/6 219/262 (83%)
Biochemical control after first 27/177 3/13 3/12 0/1 7/13 0/4 40/219 (18%)
surgery
Surgical reintervention 113/177 2/13 4/13 NA 1/7 2/6 122/219a
Biochemical control after 8/113 1/2 3/4 NA NA 0/2 12/122a
second surgery
SSA 118/208 0/14 6/12 8/8 3/13 5/6 140/262 (53%)
SSA biochemical control 0/118 0/14 1/6 0/8 NA 0/6 1/140a
PEG 37/208 0/14 2/6 4/8 1/13 2/6 46/262 (17.5%)
IGF-1 normalization with PEG 19/37 0 2/2 4/4 0/1 2/2 27/46 (58%)
RT 63/208 5/14 6/13 1/8 1/13 4/6 80/262 (30%)
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Response to RT 27/63 3/5 NA NA 1/1 2/4 33/80a

AIP mutation 42/208 NA NA 3/8 5/13 2/6 52

AIP: aryl hydrocarbon receptor-interacting protein, NA: not available, PEG: Pegvisomant, RT: radiotherapy, SSA: somatostatin analogues, TSS:
transsphenoidal surgery. a Percentage not reported due to incomplete data.

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 Pituitary gigantism: a case series

X-LAG, which may occur isolated or associated with gigantism, a pathology with a high functional and
FIPA, is characterized by pituitary adenomas or pituitary psychological impact on affected patients. Like other
hyperplasia producing most frequently increased levels case series, men were more affected than women. It is
of GH, GH releasing hormone (GHRH), and prolactin. important to note that the diagnosis was established
The patients affected by this condition exhibit rapid late (at the age of 16 years) in our population compared
growth starting in childhood. X-LAG is more frequent with other studies. TSS was the first-choice procedure,
in women and responds poorly to treatment with SSAs but given a low biochemical control rate,
(2,23,24). pharmacological therapy was often required. It should
Regarding mutations in the AIP gene, patients with be noted that the use of SSAs is less effective in
these mutations inactivating the AIP gene generally gigantism than acromegaly, and that there are no
have adenomas that produce GH and/or prolactin. significant differences in effectiveness between
Mutations of the AIP gene were reported in 5 out of available analogues. In case of lack of response to
13 patients (38%) by Nagata and cols. (14), in 3 out SSAs, the association of pegvisomant is recommended.
of 8 (38%) patients by Mangupli and cols. (6), and in Even with an adequate biochemical response and
42 out of 208 patients (20%) by Rostomyan and cols. symptom improvement, appropriate monitoring with
(3). These mutations are characterized by early onset tests should be performed due to the risk of tumor
(before the age of 20 years) and frequent occurrence growth. The use of cabergoline (in patients with
of gigantism, and for affecting males more frequently associated hyperprolactinemia) and radiotherapy as
than females. Most tumors (93%) are macroadenomas third-line management should be considered, but the
and, compared with patients without AIP mutation, high probability of radiotherapy-induced
have a more aggressive behavior including greater hypopituitarism in the pediatric population should be
extrasellar growth and lower response to surgical and taken into consideration. To avoid continued vertical
medical treatment requiring a subsequent operation, growth in patients with gigantism in cases of residual
and more frequent use of radiotherapy (2,25,26).
tumor and no response to surgery and SSA
This was evident in one of our patients (patient #1),
management, we consider that the best option in case
whom even after two surgeries showed an increase in
of residual tumors is combined therapy with SSAs and
tumor size and absence of response to SSA, but finally
pegvisomant. Pegvisomant as monotherapy can be
responded to pegvisomant and radiotherapy. For
considered in the absence of residual tumor, as well as
these reasons, early screening of relatives of affected
in patients with the AIP gene mutation, given the high
patients is important (26-28). Multiple mutations
probability of therapeutic failure of SSA.
of this gene have been described. The heterozygous
Mutations of the AIP gene should be considered in
pathogenic variant of the AIP gene c.504G>A in
familial cases of GH-producing adenomas. Multiple
exon 4 (p.Trp168*), found in our patients, has not
been previously reported in the literature or in other pathogenic variants of this gene have been described,
patients in Colombia. but this is the first time that these mutations have been
In our case series, sequencing of the AIP gene was documented in Colombia.
requested from patients #1 and #5, taking into account Ethical approval: all procedures performed in studies involving
the association of mutations of this gene with FIPA. human participants were in accordance with the ethical
Gene sequencing was also requested from all other standards of the institutional and/or national research
committee, and with the 1964 Helsinki Declaration and its later
patients, given the evidence of mutations of the AIP amendments or com-parable ethical standards.
gene in children under 18 years of age with pituitary
adenomas, and in those under 30 years of age with Informed consent: informed consent was obtained from all parti-
macroadenomas (29,30). However, this test was not cipants included in the study.
rightsreserved.

approved by the health insurance of patients #2 and

Acknowledgments: we thank the patients who agreed to partici-
pending at the time of the study, but these patients did

#3. Authorization for the test in patients #4 and #6 was

pate in the study and who consented to the publication of their
all

not follow up at our Unit. pictures, diagnostic images, and genealogical trees.
Copyright© AE&M

In conclusion, this is the largest case series

Disclosure: no potential conflict of interest relevant to this article
described to date in Colombia of patients with was reported.

392 Arch Endocrinol Metab. 2019;63/4


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